Methylphenidate (MPH, Ritalin) is a highly prescribed medication for attention deficit hyperactivity disorder, and there is also a growing problem of MPH abuse, especially among young adults. There is no evidence that therapeutic doses produce lasting neurochemical changes in humans, but this does not take in to account the possible changes induced by chronic MPH abuse, in which doses exceed 2-10 times those prescribed. Our lab has found that chronic administration of MPH in mice results in an alteration in the interaction between dopamine (DA) and serotonin (5-HT) systems such that 5-HT system activation results in DA elevations in the nucleus accumbens, which is a part of reinforcement/reward-related circuitry. Therefore it is possible that the rewarding effects of other psychostimulants may be increased after MPH exposure. It is also possible that this change could render direct and indirect 5-HT agonists rewarding, opening new categories of drugs to the potential of abuse. Our goal in this study is to understand the neurobiological mechanisms of the DA/5-HT changes induced by chronic MPH. Based on a review of the literature and data from our laboratory, we have proposed a model in which chronic MPH causes down regulation of DA D2 receptors in the dorsal raphe, resulting in decreased 5-HT release. This in turns causes postsynaptic 5-HT receptor super sensitivity, such that subsequent administration of serotonergic agonists results in hyper responsiveness of 5-HT terminal regions. In the ventral segmental area, the increased stimulation of 5-HT receptors on DA neurons would result in release of DA into terminal regions such as the nucleus accumbens, producing neurochemical effects akin to those of normal psychostimulants. We would like to test our proposed model using behavioral measures, in vivo microdialysis, and receptor auto radiography, to determine the locus of these DA and 5-HT effects, the specific receptors involved, and the behavioral results of this neurochemical change. With the growing popularity of prescription Ritalin abuse, we feel it is particularly important to study the long term effects of higher doses of Ritalin on the brain. In particular, it is important to determine whether abuse of this medication may render the brain more susceptible to the addictive properties of other stimulants.